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Gene therapy

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Gene therapy using an <a href=adenovirus v ector. A new gene is inserted into a cell using an adenovirus. If the treatment is successful, the new gene will make functional protein to treat a disease. " id="pdf-obj-0-9" src="pdf-obj-0-9.jpg">

Gene therapy using an adenovirus vector. A new gene is inserted into a cell using an adenovirus. If the treatment is successful, the new gene will make functional protein to treat a disease.

Gene therapy is the use of DNA as a pharmaceutical agent to treat disease. It derives its name from the idea that DNA can be used to supplement or alter genes within an individual's cells as a therapy to treat disease. The most common form of gene therapy involves using DNA that encodes a functional, therapeutic gene to replace a mutated gene. Other forms involve directly correcting a mutation, or using DNA that encodes a therapeutic protein drug (rather than a natural human gene) to provide treatment. In gene therapy, DNA that encodes a therapeutic protein is packaged within a "vector", which is used to get the DNA inside cells within the body. Once inside, the DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patient's disease.

Gene therapy was first conceptualized in 1972, with the authors urging caution before commencing gene therapy studies in humans. [1] The first FDA-approved gene therapy experiment in the United States occurred in 1990, when Ashanti DeSilva was treated for ADA-SCID. [2] Since then, over 1,700 clinical trials have been conducted using a number of techniques for gene therapy. [3]

Although early clinical failures led many to dismiss gene therapy as over-hyped, clinical successes since 2006 have bolstered new optimism in the promise of gene therapy. These include successful treatment of patients with the retinal disease Leber's congenital amaurosis, [4][5][6][7] X-linked SCID, [8] ADA- SCID, [9] adrenoleukodystrophy, [10] chronic lymphocytic leukemia (CLL), [11] acute lymphocytic leukemia (ALL), [12] multiple myeloma [13] and Parkinson's disease. [14] These recent clinical successes have led to a renewed interest in gene therapy, with several articles in scientific and popular publications calling for continued investment in the field. [15][16]

In 2012, Glybera became the first gene therapy treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission. [17][18]

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Scientists have taken the logical step of trying to introduce genes directly into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. However, this has proven more difficult than genetically modifying bacteria, primarily because of the problems involved in carrying large sections of DNA and delivering them to the correct site on the gene. Today, most gene therapy studies are aimed at cancer and hereditary

diseases linked to a genetic defect. Antisense therapy is not strictly a form of gene therapy, but is a related, genetically mediated therapy.

The most common form of genetic engineering involves the insertion of a functional gene at an unspecified location in the host genome. This is accomplished by isolating and copying the gene of interest, generating a construct containing all the genetic elements for correct expression, and then inserting this construct into a random location in the host organism. Other forms of genetic engineering include gene targeting and knocking out specific genes via engineered nucleases such as zinc finger nucleases, engineered I- CreI homing endonucleases, or nucleases generated from TAL effectors. An example of gene-knockout mediated gene therapy is the knockout of the human CCR5 gene in T-cells to control HIV infection. [19] This approach is currently being used in several human clinical trials. [20]

Types of gene therapy[edit source | editbeta]

Gene therapy may be classified into the two following types:

Somatic gene therapy[edit source | editbeta]

In somatic gene therapy, the therapeutic genes are transferred into the somatic cells (non sex-cells), or body, of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient's offspring or later generations. Somatic gene therapy represents the mainstream line of current basic and clinical research, where the therapeutic DNA transgene (either integrated in the genome or as an external episome or plasmid) is used to treat a disease in an individual.

Germ line gene therapy[edit source | editbeta]

In germ line gene therapy, germ cells (sperm or eggs), are modified by the introduction of functional genes, which are integrated into their genomes. Germ cells will combine to form a zygote which will divide to produce all the other cells in an organism and therefore if a germ cell is genetically modified then all the cells in the organism will contain the modified gene. This would allow the therapy to be heritable and passed on to later generations. Although this should, in theory, be highly effective in counteracting genetic disorders and hereditary diseases, some jurisdictions, including Australia, Canada, Germany, Israel, Switzerland, and the Netherlands [21] prohibit this for application in human beings, at least for the present, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations [21] and higher risk than somatic gene therapy (e.g. using non-integrative vectors). [22] The USA has no federal legislation specifically addressing human germ-line or somatic genetic modification (beyond the usual FDA testing regulations for therapies in general). [21]

Vectors in gene therapy[edit source | editbeta]

Main article: Vectors in gene therapy

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by a number of methods. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).

Main article: Viral vector

All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. Therefore this has been recognized as a plausible strategy for gene therapy, by removing the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA.

A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex virus, vaccinia, pox virus, and adeno-associated virus. [3]

Non-viral methods[edit source | editbeta]

Non-viral methods can present certain advantages over viral methods, such as large scale production and low host immunogenicity. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques that approach the transfection efficiencies of viruses.

There are several methods for non-viral gene therapy, including the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, and the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Major developments in gene therapy[edit source | editbeta]

1970s and earlier[edit source | editbeta]

In 1972 Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?" [1] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects. [23]

The first approved gene therapy case in the United States took place on 14 September 1990, at the National Institute of Health, under the direction of Professor William French Anderson. [24] It was performed on a four year old girl named Ashanti DeSilva. It was a treatment for a genetic defect that left her with ADA- SCID, a severe immune system deficiency. The effects were only temporary, but successful. [25]

New gene therapy approach repairs errors in messenger RNA derived from defective genes. This technique has the potential to treat the blood disorder thalassaemia, cystic fibrosis, and some cancers. [26] Researchers at Case Western Reserve University and Copernicus Therapeutics are able to create tiny liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane. [27]

Sickle-cell disease is successfully treated in mice. [28] The mice which have essentially the same defect that causes sickle cell disease in humans through the use a viral vector, were made to express the production of fetal hemoglobin (HbF), which normally ceases to be produced by an individual shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF has long been shown to temporarily alleviate the symptoms of sickle cell disease. The researchers demonstrated this method of gene therapy to be a more permanent means to increase the production of the therapeutic HbF. [29]

In 1992 Doctor Claudio Bordignon working at the Vita-Salute San Raffaele University, Milan, Italy performed the first procedure of gene therapy using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases. [30] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase-deficiency (SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) held from 2000 and 2002 was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the United States, the United Kingdom, France, Italy, and Germany. [31]

In 1993 Andrew Gobea was born with severe combined immunodeficiency (SCID). Genetic screening before birth showed that he had SCID. Blood was removed from Andrew's placenta and umbilical cord immediately after birth, containing stem cells. The allele that codes for ADA was obtained and was inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses entered and inserted the gene into the stem cells' chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood system via a vein. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed. [citation needed]

The 1999 death of Jesse Gelsinger in a gene-therapy experiment resulted in a significant setback to gene therapy research in the United States. [32][33] As a result, the U.S. FDA suspended several clinical trials pending the re-evaluation of ethical and procedural practices in the field. [34]

In 2003 a University of California, Los Angeles research team inserted genes into the brain using liposomes coated in a polymer called polyethylene glycol. The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the bloodbrain barrier. This method has potential for treating Parkinson's disease. [35]

RNA interference or gene silencing may be a new way to treat Huntington's disease. Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced. [36]

Scientists at the National Institutes of Health (Bethesda, Maryland) have successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells. This study constitutes one of the first demonstrations that gene therapy can be effective in treating cancer. [37]

In March 2006 an international group of scientists announced the successful use of gene therapy to treat two adult patients for a disease affecting myeloid cells. The study, published in Nature Medicine, is believed to be the first to show that gene therapy can cure diseases of the myeloid system. [38]

In May 2006 a team of scientists led by Dr. Luigi Naldini and Dr. Brian Brown from the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) in Milan, Italy reported a breakthrough for gene therapy in which they developed a way to prevent the immune system from rejecting a newly delivered gene. [39] Similar to organ transplantation, gene therapy has been plagued by the problem of immune rejection. So far, delivery of the 'normal' gene has been difficult because the immune system recognizes the new gene as foreign and rejects the cells carrying it. To overcome this problem, the HSR-TIGET group utilized a newly uncovered network of genes regulated by molecules known as microRNAs. Dr. Naldini's group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used. This work will have important implications for the treatment of hemophilia and other genetic diseases by gene therapy.

In November 2006 Preston Nix from the University of Pennsylvania School of Medicine reported on VRX496, a gene-based immunotherapy for the treatment of human immunodeficiency virus (HIV) that uses a lentiviral vector for delivery of an antisense gene against the HIV envelope. In the Phase I trial enrolling five subjects with chronic HIV infection who had failed to respond to at least twoantiretroviral regimens, a single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was safe and well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. In addition, all five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in U.S. Food and Drug Administration-approved human clinical trials for any disease. [40] Data from an ongoing Phase I/II clinical trial were presented at CROI 2009. [41]

On 1 May 2007 Moorfields Eye Hospital and University College London's Institute of Ophthalmology announced the world's first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23 year-old British male, Robert Johnson, in early 2007. [42] Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of the Moorfields/UCL trial were published in New England Journal of Medicine in April 2008. [43] They researched the safety of the subretinal delivery of recombinant adeno-associated virus (AAV) carrying RPE65 gene, and found it yielded

positive results, with patients having modest increase in vision, and, perhaps more importantly, no apparent side-effects.

In May 2008, two more groups, one at the University of Florida and another at the University of Pennsylvania, reported positive results in independent clinical trials using gene therapy to treat Leber's congenital amaurosis.

In all three clinical trials, patients recovered functional vision without apparent side-effects. [4][5][6][7] These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.

In September 2009, the journal Nature reported that researchers at the University of Washington and University of Florida were able to give trichromatic vision to squirrel monkeys using gene therapy, a hopeful precursor to a treatment for color blindness in humans. [44] In November 2009, the journal Science reported that researchers succeeded at halting a fatal brain disease,adrenoleukodystrophy, using a vector derived from HIV to deliver the gene for the missing enzyme. [45]

A paper by Komáromy et al. published in April 2010, deals with gene therapy for a form of achromatopsia in dogs. Achromatopsia, or complete color blindness, is presented as an ideal model to develop gene therapy directed to cone photoreceptors. Cone function and day vision have been restored for at least 33 months in two young dogs with achromatopsia. However, the therapy was less efficient for older dogs. [46]

In September 2010, it was announced that a patient in France had been cured of beta-thalassemia. Headed by Dr. Phillipe Leboulche, the study used a lentiviral vector to transduce the human β-globin gene into purified blood and marrow cells obtained from the patient. [47] Between 21 and 33 months after the transplant, the percentage of vector-bearing cells in his blood gradually increased, and today, the 18-year- old patient is transfusion independent (ever since June 2008). [47] His hemoglobin levels are presently stable at 9 to 10 g/dL and about a third of the hemoglobin contains the form introduced by the viral vector. [47] The clinical trial is, therefore, being heralded as a success around the world.

In 2007 and 2008, a man being treated by Gero Hütter was cured of HIV by repeated Hematopoietic stem cell transplantation (see also Allogeneic stem cell transplantation, Allogeneic bone marrow transplantation, Allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor; this cure was not completely accepted by the medical community until 2011. [48] This cure required complete ablation of existing bone marrow which is very debilitating.

In August 2011, two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The study carried out by the researchers at the University of Pennsylvania used genetically modified T cells to fight the disease. [11]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart aftermyocardial infarction. [49][50]

The FDA approves clinical trials of the use of gene therapy on thalassemia major patients in the US. Researchers at Memorial Sloan Kettering Cancer Center in New York begin to recruit 10 participants for the study in July 2012. [51] The study is expected to end in 2014. [52]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment, called Glybera, compensates for lipoprotein lipase deficiency, which can cause severe pancreatitis. [53] The recommendation was endorsed by the European Commission in November 2012 [17][18] and commercial rollout is expected in late 2013. [54]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1 which exist only on cancerous myeloma cells. This procedure had been developed by a company called Adaptimmune. [13]

In March 2013, Researchers at the Memorial Sloan-Kettering Cancer Center in New York, reported that three of five subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients immune systems would make normal T-cells and B-cells after a couple of months however they were given bone marrow to make sure. One patient had relapsed and died and one had died of a blood clot unrelated to the disease. [12]

In July 2013 the Italian San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) reported that six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months the results were promising. Three of the children had metachromatic leukodystrophy which causes children to lose cognitive and motor skills. [55] The other children had Wiskott-Aldrich syndrome which leaves them to open to infection, autoimmune diseases and cancer due to a faulty immune system. [56]

Some of the problems of gene therapy include:

Short-lived nature of gene therapy Before gene therapy can become a permanent cure for any

condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy. Immune response Any time a foreign object is introduced into human tissues, the immune system is

stimulated to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders that it has seen before makes it difficult for gene therapy to be repeated in patients. Problems with viral vectors Viruses, the carrier of choice in most gene therapy studies, present a

variety of potential problems to the patient: toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease. Multigene disorders Conditions or disorders that arise from mutations in a single gene are the best

candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy (although a 2013 trial using genes Ins and Gck reported promise in treating diabetes in dogs [57] ). For countries in which germ-line gene therapy is illegal, indications [58] that the Weismann

barrier (between soma and germ-line) can be breached are relevant; spread to the testes, therefore could impact the germline against the intentions of the therapy. Chance of inducing a tumor (insertional mutagenesis) If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients. [59][60] One possible solution for this is to add a functional tumor suppressor gene onto the DNA to be integrated; however, this poses its own problems, since the longer the DNA is, the harder it is to integrate it efficiently into cell genomes.

Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999, [61] which represented a major setback in the field. One X-SCID patient died of leukemia following gene therapy treatment in 2003. [2] In 2007, a rheumatoid arthritis patient died from an infection in a gene therapy trial; a subsequent investigation concluded that the death was not related to her gene therapy treatment. [62]

Preventive gene therapy[edit source | editbeta]

Preventive gene therapy is the repair of a gene with a mutation associated with a progressive disease, prior to the expression of a medical condition, to prevent that expression.

One case study of preventive gene therapy: Retinitis Pigmentosa

Blindness can be caused by multiple genetic diseases. Many gene therapy efforts have been focused on treating blindness as a result of moderate success in preventing the loss of vision in multiple animal models. To do this, blindness must be diagnosed early on before the symptoms begin. The retina, which is located in the back of the eyeball, is the first step in processing visual information, accordingly it is a common target in exploration of the genetic issue that leads to blindness. One autosomal genetic disease that has been extensively researched is retinitis pigmentosa (RP) because it has excellent animal models for genetic therapy techniques to treat blindness.

Within a single disease, there can be multiple preventative gene therapy strategies used to combat the progression of the symptoms. Most people who suffer from RP are born with rod cells that are either dead or dysfunctional, so they are effectively blind at nighttime, since these are the cells responsible for vision in low levels of light. What follows often is the death of cone cells, responsible for color vision and acuity, at light levels present during the day. Loss of cones leads to full blindness as early as five years old, but may not onset until many years later. There have been multiple hypotheses about how the lack of rod cells can lead to the death of cone cells. Pinpointing a mechanism for RP is difficult because there are more than 39 genetic loci and genes correlated with this disease. In an effort to find the cause of RP, there have been different gene therapy techniques applied to address each of the hypotheses. [63]

One hypothesis is that when the rod cells die, there is no longer a critical growth factor secreted for proper cone function and survival. Some scientists have experimented with treating this issue by injecting substitute trophic factors into the eye. One group of researchers injected the rod derived cone viability factor (RdCVF) protein (encoded for by the Nxnl1 (Txnl6) gene) into the eye of the most commonly occurring dominant RP mutation rat models. This treatment demonstrated success in promoting the survival of cone activity, but the treatment served even more significantly to prevent progression of the disease by increasing the actual function of the cones. [64] Two of the major issues encountered when trying to inject these desirable proteins, is that they are both difficult to purify and difficult to deliver multiple times as a consistent treatment. Researchers are currently trying to develop an adeno-associated virus (AAV) vector to use for such treatments to address these problems. Injection of an AAV vector encoding this factor might only have to happen once.

Another issue is choosing which protein to inject. Multiple candidates such as brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), and pigment epithelium derived factor (PEDF) have demonstrated functional success within the eye when they are delivered to the subretinal region. One of the most successful proteins of those aforementioned, is ciliary neurotrophic factor (CNTF). CNTF has shown success of slowing retinal degradation in 13 different animal models. CNTF is currently being used as a treatment in human clinical trials. [65] In Phase I of the clinical trial, there were 10 participants suffering from advanced RP who each had one of their eyes implanted with CNTF encapsulated cell devices for six months, followed by explantation. Five of the participants received higher dose implants of CNTF, and the other five received an approximately five times smaller dose

implant. Multiple participants displayed improved acuity both while the implant was in the eye, and one month later when retested. In some of the other animal models, high doses of CNTF have demonstrated increased photoreceptor metabolic activity, which suggests that it is possible for CNTF to increase photoreceptor metabolic activity in human damaged cones as well. CNTF could improve metabolic activity in photoreceptor cones to the extent that it improves visual acuity, as seen in several of the participants who performed significantly better on the letter recognition task compared to their respective pretreatment baseline. Although not all of the participants experienced a significant increase in visual acuity, this method of encapsulated implantations poses an intriguing line of research. It offers the advantage of being reversible, as one can remove the encapsulated cells should anything go wrong. Gene therapy using viral vectors to deliver a therapeutic gene is not obviously reversible.

In popular culture[edit source | editbeta]

In the TV series Dark Angel gene therapy is mentioned as one of the practices performed on

transgenics and their surrogate mothers at Manticore, and in the episode Prodigy, Dr. Tanaka uses a groundbreaking new form of gene therapy to turn Jude, a premature, vegetative baby of a crack/cocaine addict, into a boy genius. Gene therapy is a crucial plot element in the video game Metal Gear Solid, where it has been used to

illegally enhance the battle capabilities of soldiers within the US military, and their Next Generation Special Forces units. Gene therapy plays a major role in the sci-fi series Stargate Atlantis, as a certain type of alien

technology can only be used if one has a certain gene which can be given to the members of the team through gene therapy involving a mouse retrovirus. Gene therapy also plays a major role in the plot of the James Bond movie Die Another Day, where a

scientist has developed a means of altering peoples' entire appearances through the use of DNA samples acquired from others- generally homeless people that would not be missed- that are subsequently injected into the bone marrow, the resulting transformation apparently depriving the subjects of the ability to sleep. Gene therapy plays a recurring role in the present-time sci-fi television program ReGenesis, where it is

used to cure various diseases, enhance athletic performance and produce vast profits for bio-tech corporations. (e.g. an undetectable performance-enhancing gene therapy was used by one of the characters on himself, but to avoid copyright infringement, this gene therapy was modified from the tested-to-be-harmless original, which produced a fatal cardiovascular defect) Gene therapy is the basis for the plot line of the film I Am Legend. [66]

Gene therapy is an important plot key in the game Bioshock where the game contents refer

to plasmids and [gene] splicers. The book Next by Michael Crichton unravels a story in which fictitious biotechnology companies experiment with gene therapy.

In the television show Alias, a breakthrough in molecular gene therapy is discovered, whereby a

patient's body is reshaped to identically resemble someone else. Protagonist Sydney Bristow's best friend was secretly killed and her "double" resumed her place. In the 2011 film Rise of the Planet of the Apes, a fictional gene therapy called ALZ-112 was a drug that was a possible cure for Alzheimer's disease, the therapy increased the host's intelligence and made their irises green, along with the revised therapy called 113 which increased intelligence in apes yet was a deadly, internal virus in humans.